【作者】 张俊；

【导师】 彭文兴；

【作者基本信息】 中南大学 ， 药剂学， 2011， 硕士

【摘要】 一、目的建立一种可靠、高效、简便的UPLC-MS/MS方法,测定米格列奈在人血浆中的浓度,考察米格列奈钙片在健康受试者体内的药物动力学特性。24名健康受试者分别在空腹和餐状态下给予米格列奈钙片剂,考察食物及性别对单次递增剂量的米格列奈钙片药动学的影响。二、方法1.1测定方法血浆样品以乙腈蛋白沉淀法处理,以那格列奈为内标,采用UPLC-MS/MS法测定血浆中米格列奈的浓度。1.2给药方法采用随机,单次给药(3个剂量组),双周期交叉自身对照的设计,24名健康志愿受试者第一周期分别在禁食一夜(空腹)或低脂早餐后(餐后)单次口服5、10、20 mg的米格列奈钙；经7天的洗脱期后,第二周期志愿者在餐后或空腹状态下给予同样剂量的药物。1.3生物样本采集米格列奈钙血样分别于试验当天早晨米格列奈钙服药前0小时(h)及服药后5,10,15,20,30,45分钟(min)和1,1.5,2,3,4,6,8 h取静脉血4 mL。置肝素试管中,离心分离出血浆,置-70℃冰箱中保存至测定。1.4不良反应监测受试者服用米格列奈钙后,于2和6 h分别监测血压,心率,心电图,记录各项不良反应。三、结果1.米格列奈的测定米格列奈在10.0～7000.0ng/mL浓度范围内线性关系良好,最低检测浓度为10.0 ng/mL。萃取回收率均在89.06%～99.81%之间,方法回收率在86.00%～112.00%之间,日内、日间RSD均不高于12.49%,低,中,高三种浓度的质控样品稳定性良好,变异均不高于10.51%。2.食物对米格列奈钙药动学的影响24名健康志愿者,分为3组,每组8人[男女各半]。受试者单次空腹和餐后口服米格列奈钙后,与空腹组相比较,餐后服用米格列奈钙使Cmax减小了60.4%-65.2%(5 mg：60.4%,10 mg：64.9%,20 mg：65.2%)；餐后服用米格列奈使Tmax延长了0.88-1.68 h(5 mg：1.75 h vs0.36 h；10 mg：1.97 h vs 0.29 h和20mg：1.18 h vs 0.30 h)；餐后和空腹状态的AUCs值相似；食物不影响米格列奈钙的体内消除。3.性别对米格列奈钙药动学的影响无论受试者是空腹状态还是餐后状态服用米格列奈钙,同一剂量组受试者两个周期、餐后和空腹的平均药动学参数值均无统计学差异(P>0.05)。因此,性别不影响米格列奈钙的药动学参数。4.不良事件米格列奈钙片剂耐受性良好,整个试验过程中,未见任何与药物相关的严重不良事件的发生。四、结论1.方法学本研究建立的UPLC-MS/MS具有较好的灵敏度及专属性,样品处理简单,大大缩短了分析测定时间。在实际应用中,此方法能够满足米格列奈钙的临床药物动力学的研究。2.药动学本文报道了食物与性别对米格列奈钙在中国健康人体内的药动学的影响。在整个试验中,食物影响5 mg,10 mg和20 mg的米格列奈钙在健康受试者体内的口服吸收速度,不影响三个剂量组药物在受试者体内的吸收程度,但无论是健康受试者空腹或餐后口服米格列奈钙,性别均不影响其药动学参数。3.安全性整个试验过程受试者对三个剂量组药物均能很好的耐受。更多还原

【Abstract】 OBJECTIVESTo establish a reliable, efficient and simple ultra performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) method for the determination of mitiglinide (MGN) in human plasma; The volunteers received the same dose under the fed or fasted condition, to assess the effects of food and gender on the pharmacokinetic (PK) properties of MGN calcium tablets.METHODS1.1 Determination of MGN in human plasmaPlasma sample preparation was performed by using protein precipitation. Nateglinide used as the internal standard (IS). Concentrations of MGN in plasma were determined using UPLC-MS/MS.1.2 Dose administration In this open-label, randomized, single-dose (3 distinct doses),2-way crossover PK study, three doses of MGN calcium 5,10 or 20 mg were administered to healthy adult volunteers after an overnight fast (fasted condition) or low-fat breakfast (fed condition) (period 1). After 7 days, the participants received the same dose under the opposite fed/fasted condition (period 2).1.3 Biology samples collectionSerial blood samples were collected from an in-dwelling venous catheter (anticoagulated with sodium heparin) at 5,10,15,20,30,45 min and 1,1.5,2,3,4,6,8h before and after MGN calcium administration. Blood samples were collected in plastic containers, and immediately centrifuged. The separated plasma samples were immediately frozen at-70℃until assayed.1.4 Safety monitoringAdverse event was elicited from the volunteers by means of spontaneous report and specific questioning. Serial measurements of blood pressure, heart rate, and ECG were recorded 2 and 6 h after MGN administration.RESULTS1. Determination of MGN The standard calibration curve was linear (range,10.0-7000.0 ng/mL) for MGN (r2=0.999 8, n=7). The lower limit of quantification (LLOQ) was 10.0 ng/mL. The extraction recovery and methodology recovery ranged from 89.06% to 99.81%, and 86.00% to 112.00%, respectively. The intraday and interday relative standard deviation (RSD) were≤12.49%. The stability tests showed that the plasma samples of MGN were all stable under different conditions(RSD≤8.14%).2. The effects of food on the PK of MGN calciumA total of twenty-four Chinese volunteers 8 [4 men,4 women] volunteers per group were enrolled in the study. Food reduced the Cmax of rapidly absorbed MGN calcium by 60.4% to 65.2%(5 mg:60.4%,10 mg: 64.9%,20 mg:65.2%). The mean Tmax was significantly delayed form 0.88h to 1.68 h by the presence of food compared with fasting conditions (5mg:1.75h vs 0.36h; 10mg:1.97h vs 0.29h and 20mg:1.18h vs 0.30 h). However, the extent of MGN calcium absorption did not appear to change as evidenced by similar AUCs for fasted and fed conditions.3. The effects of gender on the PK of MGN calciumThere were no significant gender differences found in the PK properties of MGN in either fasted or fed states in the some dose group (P>0.05). Gender did not appear to affect the PK properties of MGN calcium. 3. Adverse events assessmentThe drug was well tolerated, and no drug-related serious adverse events were reported in the whole test.CONCLUSIONS1. MethodsThe UPLC-MS/MS method that was developed for this study used a simple technique for sample preparation and was associated with good sensitivity, reproducibility, and specificity. It can be used for the PK study of MGN calcium.2. PK testWe reported the effects of food and gender on the PK profile of MGN calcium tablets after single oral administration in healthy adults. In this PK study, food intake did not appear to affect the extent of absorption (ie, total exposure) of single doses of MGN calcium 5 mg,10 mg and 20 mg in these healthy adult volunteers. But it affected the absorption rate of oral MGN calcium at all the three doses. Gender did not appear to affect the PK properties of MGN calcium in both states.3. Safety testThe three single doses appeared to be well tolerated.更多还原